Legionella pneumophila is an important cause of epidemic and sporadic human pneumonia. Acute inflammatory infiltrate fills airspaces with exudate, alveolar macrophages and PMN; alveolar cell damage and interstitial edema and inflammation may ensue. Critical interactions between cellular host defenses and legionella can only be inferred but not proven from study of clinical material. Exposure of normal human and animal cells to Legionella in vitro suggests that the bacterium is a facultative intracellular parasite that multiplies within non-activated AM, but is inhibited (although not killed) by activated AM and by PMN. We have established an aerosol model of legionella penumonia in two species of animals (guinea pig and Lewis rat) that vary greatly in their susceptibility to the bacterium. The aerosol mode of infection has great advantages over other routes, because it mimics a documented natural route of infection and does not interfere with host defenses in the early hours after infection. We have characterized the model and have used bronchoalveolar lavage to study the interactions of cells from the airspaces with bacteria that have been presented by aerosol. Our initial data suggest that the AM is a site of replication of bacteria and that the appearance of the PMN is associated with the first evidence of an effective host defense. We plan to manipulate the animal model to determine the importance of cellular host defenses, to examine the effects of developing immunity on the efficacy of the phagocytic response, and to assess the expected increment in cellular defenses in an animal that has been previously infected with the homologous organism. We will use in vitro techniques to study the interactions of bacteria and cells from normal and infected animals in an attempt to bridge the gap between in vitro and in vivo observations. The mechanisms of fluid accumulation cannot be studied in vitro and are difficult to determine in human material. Exudation will be examined, and whether increased vascular depends on the generation of a cellular inflammatory response will be assessed. Continued exploration of pathogenetic mechanisms in this infection will provide a basis for a more rational approach to management of human infection and should increase our understanding of the biology of facultatively intracellular bacteria.